Oropharyngeal and vulvovaginal candidiasis (OPC and VVC), mucosal infections caused by Candida albicans, are the leading opportunistic infections among HIV-infected persons. In most humans, C. albicans is a harmless commensal of the gastrointestinal tract. The mechanisms by which the organism switches to an invasive pathogen are poorly understood. We hypothesize that pathogenesis at the oral and vaginal mucosa is facilitated by the expression of a subset of candidal genes that are specific to the mucosal surfaces. The major overall objective of our laboratory is to understand C. albicans gene expression during the pathogenesis of human infections. The goal of this R21 project is to identify C. albicans genes that are specifically expressed at the oral and/or vaginal mucosa, in order to identify genes that contribute to the pathogenesis of HIV associated candidiasis. To accomplish this, we will use saliva and vaginal fluid that are rich in locally produced anti-candidal antibodies to identify immunogenic C. albicans antigens. In preliminary studies, we created separate pools of saliva and vaginal fluid from HIV-infected persons with active OPC and VVC, respectively. The pooled samples were adsorbed against yeast and hyphae of C. albicans strains grown in vitro, as well as cell lysates.
In Specific Aim 1, we will use the adsorbed samples, now concentrated in antibodies directed against antigens expressed uniquely within the human host, to screen a C. albicans genomic expression library in parallel. The complete sequences of the genes encoding immunogenic antigens will be identified using the C. albicans sequence databases.
In Specific Aim 2, we will confirm that these genes are induced at the oral or vaginal mucosa, but not during routine growth in vitro, using quantitative real-time reverse transcription-polymerase chain reaction. We will also directly detect the in vivo induced antigens by using routine antibodies raised against the purified antigens to probe OPC and VVC samples recovered from HIV-infected persons. The mucosal-specific genes identified in this project will be studied in future projects for their specific roles during candidal pathogenesis, with the ultimate goal of designing strategies to treat and prevent OPC and VVC.
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| Badrane, Hassan; Cheng, Shaoji; Nguyen, M Hong et al. (2005) Candida albicans IRS4 contributes to hyphal formation and virulence after the initial stages of disseminated candidiasis. Microbiology 151:2923-31 |
| Cheng, Shaoji; Clancy, Cornelius J; Checkley, Mary Ann et al. (2005) The role of Candida albicans NOT5 in virulence depends upon diverse host factors in vivo. Infect Immun 73:7190-7 |
